Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma

Pommerenke, Claudia; Hauer, Vivien; Zaborski, Margarete; MacLeod, Roderick A.F.; Nagel, Stefan; Amini, Rose‐Marie; Berglund, Mattias; Geffers, Robert; Drexler, Hans G.; Quentmeier, Hilmar

doi:10.1038/bcj.2016.43

Cited by 8 publications

(9 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Actually, exosomal mRNA were reported to reflect the cell of origin in a previous study investigating the exosomes of DLBCL cell lines [33]. Likewise, prior to conducting this study using patient serum samples, we identified the RPS25/FOXR1 fusion in exosomal mRNA isolated from the DLBCL cell line U-2932, as previously reported [30].…”

Section: Discussionsupporting

confidence: 56%

See 1 more Smart Citation

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma

Bang¹,

Shim²,

Ryu³

et al. 2022

J. Cancer

View full text Add to dashboard Cite

Background:The clinical utility of mRNA cargo in exosomes is unclear, although exosomes have potential as non-invasive biomarkers. This study aimed to investigate the feasibility of exosomal mRNA sequencing for monitoring disease status and predicting outcomes in non-Hodgkin lymphoma (NHL) patients. Methods: Exosomes were isolated from archived serum samples of 33 patients with NHL who were registered into our prospective cohort: diffuse large B-cell lymphoma (DLBCL, n = 17), intravascular B-cell lymphoma (IVL, n = 1), primary mediastinal large B-cell lymphoma (PMBL, n = 4), follicular lymphoma (FL, n = 3), mantle cell lymphoma (MCL, n = 3), and extranodal NK/T-cell lymphoma (ENKTL, n = 5). Exosomal mRNA sequencing was performed, and its concordance with clinical course was analyzed and compared with those of circulating tumor DNA (ctDNA) mutations. Results: Exosomal mRNA sequencing was performed successfully in 26 cases (79%, 26/33), whereas the remaining seven cases were not completed due to their small amount of RNA. The exosomal mRNA sequencing of DLBCL showed gene expression profiles consistent with activated B-cell-like and germinal center type. The longitudinal assessment of exosomal mRNA sequencing results in accordance with the clinical course showed that the post-treatment changes of exosomal mRNA expression were more consistent with treatment outcome than were those of ctDNA mutations. In particular, the exosomal mRNA expression of genes such as BCL2 and BCL6 was increased at the time of disease progression in DLBCL and FL patients. Conclusions: This study demonstrated the feasibility of exosomal mRNA expression profiles as a biomarker for NHL patients. Our results might provide the rationale for studies to explore the potential of exosomal mRNA as a biomarker in NHL patients.

show abstract

Section: Discussionsupporting

confidence: 56%

“…The sequencing of U2932 exosomal mRNA identified the fusion of RPS25/FOXR1 (Figure 1H). This result supported that exosomal cargo can contain the mRNA of tumor cells, and that exosomal mRNA sequencing could represent the mRNA expression of tumor cells because this fusion was confirmed in the U2932 cell line [30].…”

Section: Serum-derived Exosomessupporting

confidence: 62%

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma

Bang¹,

Shim²,

Ryu³

et al. 2022

J. Cancer

View full text Add to dashboard Cite

show abstract

“…Although aberrant methylation of these candidate genes, including FOXO3 and TERT, has previously been reported in MDS (19,20), most others remain to be elucidated. Interestingly, some of these genes, such as LEP, ALOX12, RARRES2, DLEU7, and FOXR1, have been reported to be associated with other hematologic malignancies, including AML, chronic lymphocytic leukemia (CLL), and B-cell lymphoma (15,(21)(22)(23)(24). Moreover, methylations in RARRES2, REC8, WNK2, and PANX2 have been demonstrated with potential roles in solid cancers (25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome DNA Methylation Sequencing Reveals Epigenetic Changes in Myelodysplastic Syndromes

Zhou

Jin

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

Epigenetic dysregulation of cancer-associated genes has been identified to contribute to the pathogenesis of myelodysplastic syndromes (MDS). However, few studies have elucidated the whole-genome DNA methylation in the initiation pathogenesis of MDS. Reduced representation bisulfite sequencing was performed in five de novo MDS patients and four controls to investigate epigenetic alterations in MDS pathogenesis. The mean global methylation in five MDS patients showed no significant difference compared with the four controls. In depth, a total of 1,459 differentially methylated fragments, including 759 hypermethylated and 700 hypomethylated fragments, were identified between MDS patients and controls. Targeted bisulfite sequencing further identified that hypermethylation of DLEU7, FOXR1, LEP, and PANX2 were frequent events in an additional cohort of MDS patients. Subsequently, LEP hypermethylation was confirmed by real-time quantitative methylation-specific PCR in an expanded cohort of larger MDS patients. In clinics, LEP hypermethylation tended to be associated with lower bone marrow blasts and was significantly correlated with U2AF1 mutation. Survival analysis indicated that LEP hypermethylation was associated with a markedly longer survival time but was not an independent prognostic biomarker in MDS patients. Functional studies revealed pro-proliferative and anti-apoptotic effects of leptin in the MDS cell line SKM-1, and it was significantly associated with cell growth and death as well as the Toll-like receptor and NF-kappa B signaling pathways. Collectively, our findings demonstrated that whole-genome DNA methylation analysis identified novel epigenetic alterations such as DLEU7, FOXR1, LEP, and PANX2 methylations as frequent events in MDS. Moreover, LEP might play a role in MDS pathogenesis, and LEP hypermethylation was associated with longer survival but not as an independent prognostic biomarker in MDS.

show abstract

“…Several studies have shown that mouse Foxr1 is involved in spermiogenesis [ 30 ]. In addition, several point mutations within human FOXR1 have been shown to be associated with a variety of carcinomas, although functional characterization of these oncogenic FOXR1 mutants has not been performed [ 31 – 33 ]. Recently, Foxr1 was found to be an essential maternal–effect gene in zebrafish that is required for proper cell division and survival [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

FOXR1 regulates stress response pathways and is necessary for proper brain development

et al. 2021

View full text Add to dashboard Cite

The forkhead box (Fox) family of transcription factors are highly conserved and play essential roles in a wide range of cellular and developmental processes. We report an individual with severe neurological symptoms including postnatal microcephaly, progressive brain atrophy and global developmental delay associated with a de novo missense variant (M280L) in the FOXR1 gene. At the protein level, M280L impaired FOXR1 expression and induced a nuclear aggregate phenotype due to protein misfolding and proteolysis. RNAseq and pathway analysis showed that FOXR1 acts as a transcriptional activator and repressor with central roles in heat shock response, chaperone cofactor-dependent protein refolding and cellular response to stress pathways. Indeed, FOXR1 expression is increased in response to cellular stress, a process in which it directly controls HSPA6, HSPA1A and DHRS2 transcripts. The M280L mutant compromises FOXR1’s ability to respond to stress, in part due to impaired regulation of downstream target genes that are involved in the stress response pathway. Quantitative PCR of mouse embryo tissues show Foxr1 expression in the embryonic brain. Using CRISPR/Cas9 gene editing, we found that deletion of mouse Foxr1 leads to a severe survival deficit while surviving newborn Foxr1 knockout mice have reduced body weight. Further examination of newborn Foxr1 knockout brains revealed a decrease in cortical thickness and enlarged ventricles compared to littermate wild-type mice, suggesting that loss of Foxr1 leads to atypical brain development. Combined, these results suggest FOXR1 plays a role in cellular stress response pathways and is necessary for normal brain development.

show abstract

Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma

Cited by 8 publications

References 9 publications

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma

Clinical relevance of serum-derived exosomal messenger RNA sequencing in patients with non-Hodgkin lymphoma

Whole-Genome DNA Methylation Sequencing Reveals Epigenetic Changes in Myelodysplastic Syndromes

FOXR1 regulates stress response pathways and is necessary for proper brain development

Contact Info

Product

Resources

About